Design, synthesis, pharmacology, and structural analysis of bioactive melanocortin receptors' ligands by hybrid approaches

Persistent Link:
http://hdl.handle.net/10150/284287
Title:
Design, synthesis, pharmacology, and structural analysis of bioactive melanocortin receptors' ligands by hybrid approaches
Author:
Han, Guoxia
Issue Date:
2000
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
A number of alpha-melanotropin (α-MSH) analogues have been designed de novo, synthesized and bioassayed at different melanocortin receptors from frog skins, mice and humans. These ligands were designed from two scaffolds, Somatostatin and Deltorphin-II, by two new hybrid approaches, one of which utilizes the modified cyclic structure (H-DPhe-Cys---Cys-Thr-NH₂) of a Somatostatin analogue--Sandostatin®, while the other incorporates the hydrophobic tail of Deltorphin-II (Glu-Val-Val-Gly-NH₂). Some of the ligands designed, H-DPhe-c [XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH₂ [XXX and AAA = Cys, DCys, Pen, DPen; YYY = His, His(1-Me), His(3-Me); ZZZ = Phe and side chain halogen substituted Phe, DPhe, DNal(1') and DNal(2 ')] and c[XXX-YYY-ZZZ-Arg-Trp-Glu]-Val-Val-Gly-NH₂ [XXX = nothing, Gly, β-Ala, γ-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (CPG); ZZZ = Phe, DPhe; DNal(2')], show unique selectivity and potency among the receptors tested. In particular, one of the ligands, Delt-38B--c[Gly-CPG-DNal(2')Arg-Trp-Glu]-Val-Val-Gly-NH₂, is a human melanocortin receptor (hMC1R) antagonist (IC₅₀ = 12 nM) the first potent hMC1R antagonist discovered. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs. In addition, the structures of some of the ligands have been analyzed by high field solution NMR and their conformation evaluated by modeling with MacroModel. The conformations obtained from these methods help us better understand the structural basis the selectivities and ligand-receptor interactions.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Biochemistry.; Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleDesign, synthesis, pharmacology, and structural analysis of bioactive melanocortin receptors' ligands by hybrid approachesen_US
dc.creatorHan, Guoxiaen_US
dc.contributor.authorHan, Guoxiaen_US
dc.date.issued2000en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractA number of alpha-melanotropin (α-MSH) analogues have been designed de novo, synthesized and bioassayed at different melanocortin receptors from frog skins, mice and humans. These ligands were designed from two scaffolds, Somatostatin and Deltorphin-II, by two new hybrid approaches, one of which utilizes the modified cyclic structure (H-DPhe-Cys---Cys-Thr-NH₂) of a Somatostatin analogue--Sandostatin®, while the other incorporates the hydrophobic tail of Deltorphin-II (Glu-Val-Val-Gly-NH₂). Some of the ligands designed, H-DPhe-c [XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH₂ [XXX and AAA = Cys, DCys, Pen, DPen; YYY = His, His(1-Me), His(3-Me); ZZZ = Phe and side chain halogen substituted Phe, DPhe, DNal(1') and DNal(2 ')] and c[XXX-YYY-ZZZ-Arg-Trp-Glu]-Val-Val-Gly-NH₂ [XXX = nothing, Gly, β-Ala, γ-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (CPG); ZZZ = Phe, DPhe; DNal(2')], show unique selectivity and potency among the receptors tested. In particular, one of the ligands, Delt-38B--c[Gly-CPG-DNal(2')Arg-Trp-Glu]-Val-Val-Gly-NH₂, is a human melanocortin receptor (hMC1R) antagonist (IC₅₀ = 12 nM) the first potent hMC1R antagonist discovered. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs. In addition, the structures of some of the ligands have been analyzed by high field solution NMR and their conformation evaluated by modeling with MacroModel. The conformations obtained from these methods help us better understand the structural basis the selectivities and ligand-receptor interactions.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Biochemistry.en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.identifier.proquest9992118en_US
dc.identifier.bibrecord.b41170696en_US
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